MST1R (macrophage stimulating 1 receptor; human MST1R is shown in GenBank® accession No; NM_002447.2), also described as RON or CDw136, is a c-Met related tyrosine kinase found on cells of epithelial origin. The 1400 amino acid single chain precursor is cleaved into a disulfide-linked heterodimer consisting of an extracellular 40kDa α-chain and a 150kDa β-chain, which includes the intracellular tyrosine kinase domain. Similar to c-Met, MST1R induces invasive cell growth, migration, cell dissociation and matrix invasion. [Wang, et al., Carcinogenesis 24, 1291-1300, 2003; Lee, et al., Clin Cancer Res 11, 2222-2228, 2005]. Both tyrosine kinases are overexpressed on a variety of malignant tumors, such as breast, lung or prostate cancer [O'Toole, et al., Cancer Res 66, 9162-9170, 2006]. MSP, macrophage stimulatory protein, is the only ligand to MST1R known so far. MSP binding triggers autophosphorylation of the MST1R tyrosine kinase domain. Thereby activated MST1R transduces a variety of different pathway cascades. [Wang, et al., Carcinogenesis 24, 1291-1300, 2003; O'Toole, et al., Cancer Res 66, 9162-9170, 2006]. Generation of biologically active, truncated MST1 R variants through mRNA splicing has also been reported [Wang, et al., Carcinogenesis 24, 1291-1300, 2003]. For example, MST1R160 variant was found in some of colorectal carcinoma samples, and its overexpression without ligand mediated tumor formation in nude mice [Zhou et al., Oncogene 22, 186-197, 2003]. Anti-MST1R antibodies like IMC-41A10 block the ligand-receptor interaction and are potent inhibitors of receptor and downstream signaling, cell migration and tumorigenesis [O′Toole, et al., Cancer Res 66, 9162-9170, 2006].
In conclusion, antibodies blocking MST1R activity are of potential therapeutic relevance in human cancer.